Genetic Variant INSL3:p.Arg50ProfsTer16 (chr19-17821363-G-GC) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PVS1_StrongPP5_ModerateBS2_Supporting

The NM_005543.4(INSL3):c.143dupG(p.Arg50ProfsTer16) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000646 in 1,548,608 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 35)

Exomes 𝑓: 0.000064 ( 0 hom. )

Consequence

INSL3
NM_005543.4 frameshift

Scores

Not classified

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 0.443

Publications

1 publications found

Variant links:

Genes affected

INSL3 (HGNC:6086): (insulin like 3) This gene encodes a member of the insulin-like hormone superfamily. The encoded protein is mainly produced in gonadal tissues. Studies of the mouse counterpart suggest that this gene may be involved in the development of urogenital tract and female fertility. This protein may also act as a hormone to regulate growth and differentiation of gubernaculum, and thus mediating intra-abdominal testicular descent. Mutations in this gene may lead to cryptorchidism. Alternate splicing results in multiple transcript variants. [provided by RefSeq, May 2012]

INSL3 Gene-Disease associations (from GenCC):

cryptorchidism
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

INSL3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 7 pathogenic variants in the truncated region.

PP5

Variant 19-17821363-G-GC is Pathogenic according to our data. Variant chr19-17821363-G-GC is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2429748.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 10 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005543.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INSL3	NM_005543.4	MANE Select	c.143dupG	p.Arg50ProfsTer16	frameshift	Exon 1 of 2	NP_005534.2
	INSL3	NM_001265587.2		c.143dupG	p.Arg50ProfsTer33	frameshift	Exon 1 of 3	NP_001252516.1	P51460-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
INSL3	ENST00000317306.8	TSL:1 MANE Select	c.143dupG	p.Arg50ProfsTer16	frameshift	Exon 1 of 2	ENSP00000321724.6	P51460-1
INSL3	ENST00000379695.5	TSL:1	c.143dupG	p.Arg50ProfsTer33	frameshift	Exon 1 of 3	ENSP00000369017.4	P51460-2
INSL3	ENST00000598577.1	TSL:1	c.140dupG	p.Arg49fs	frameshift	Exon 1 of 2	ENSP00000469309.1	M0QXQ3

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000774

AC:

AN:

142076

AF XY:

0.0000522

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000283

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000156

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000645

AC:

AN:

1396396

Hom.:

Cov.:

AF XY:

0.0000770

AC XY:

AN XY:

688752

show subpopulations

African (AFR)

AF:

0.0000317

AC:

AN:

31558

American (AMR)

AF:

0.00

AC:

AN:

35676

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25126

East Asian (EAS)

AF:

0.0000840

AC:

AN:

35718

South Asian (SAS)

AF:

0.00

AC:

AN:

79192

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47106

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5574

European-Non Finnish (NFE)

AF:

0.0000788

AC:

AN:

1078518

Other (OTH)

AF:

0.0000173

AC:

AN:

57928

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41464

American (AMR)

AF:

0.0000654

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000793

ClinVar

ClinVar submissions as Germline

Significance:Likely pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Bilateral cryptorchidism (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.44

Mutation Taster

=103/97

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

19-17821363-GC-GCC

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over